Invited Commentaries Commentary: assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers M. H. Miller & J. F. Dillon Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. E-mail: m.miller@dundee.ac.uk doi:10.1111/apt.12134 We read with great interest the article by Shen et al. 1 The authors describe the diagnostic utility of CK18 (M30, M65 and M65ED) for the diagnosis of NAFLD and NASH. CK 18 was first described in this context by Wie- ckowska et al. 2 in 2007. In their seminal paper, CK18 fragments were shown to be markedly increased in patients with NASH as compared with simple steatosis and control. In patients with NAFLD, CK18 achieved an AUC of 0.93 for the diagnosis of NASH. In a further, larger scale (n = 139) validation study, Feldstein et al. 3 found that CK18 fragments achieved an AUC of 0.83 for diagnosing NASH. Both studies described the progressive relationship between CK18 and fibrosis grade. Since then, CK 18 has been validated in a number of other studies, with AUC values ranging from 0.83 to 0.88. 4–6 In this current study, Shen et al. report impressive AUC values for the diagnosis of NAFLD from a control population for all three biomarkers (0.92–0.94); however, the AUC for NASH diagnosis drops to a disappointing 0.66–0.71. These are values lower than reported in other validation studies. A potential explanation is the unclear description of NASH. NASH was diagnosed in the pres- ence of steatosis, lobular inflammation and hepatocyte ballooning, but it was not clear if this constituted an NAS score  5, or if it included the NAS score 3–4 cases. This paper introduces an additional use for CK18 fragments; they measured the three biomarkers in paired patient samples 36 months apart, a novel observation. Of the 51 patients analysed, 10 progressed from non-NASH to NASH. Within this cohort, the three biomarkers had AUC of 0.74–0.82 for the prediction of progression. This is novel for CK18-based markers and, despite the small numbers included in this sub-analysis, is worthy of note and future study. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Shen J, Chan HL-Y, Wong GL-H, et al. Assessment of non- alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliment Pharmacol Ther 2012; 36: 1057–66. 2. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006; 44: 27–33. 3. Feldstein AE, Wieckowska A, Lopez AR, Liu Y-C, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50: 1072–1078. 4. Yilmaz YDE, Ulukaya E, Akgoz S, et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 2007; 13: 837–44. 5. Tamimi TIA-R, Elgouhari HM, Alkhouri N, et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol 2011; 54: 1224–1229. 6. Diab DL, Yerian L, Schauer P, et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clin Gastroenterol Hepatol 2008; 6: 1249–1254. AP&T invited commentary and correspondence columns are restricted to letters discussing papers that have been pub- lished in the journal. A letter must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt. ª 2012 Blackwell Publishing Ltd 275 Alimentary Pharmacology and Therapeutics